Antibodies to nucleic acids are important diagnostically and pathogenetically in systemic lupus. Patients with active SLE have an increase in DNA in immune complexes. Such DNA is enriched in guanine (G) and cytosine (C). Low molecular weight DNA enriched in G-C is released from SLE leukocytes. This DNA may be important in the pathogenesis of SLE. Genes favoring the production of anti-DNA may include those which lead to the release of immunogenic DNA. In mice a subset of B cells is responsible for anti-DNA production. In NZB mice, B cells can transfer anti-DNA to congenic NZB.xid recipients. This transfer is prevented by treating either donors animals or recipients with anti-Ia antibodies. Similar approaches to human disease are being sought. In autoimmune mice, polyclonal B cell activation, rather than specific immunization, is the major contributor to anti-DNA hyperproduction. Patients with SLE have greater repertoire differences than mice. The differences are in IgG but not IgM autoantibodies. In these individuals specific immunization or cross-reactive immunization may also play a critical role in autoantibody production.